Technical Field
The present invention relates generally to PEGylated tyrosyl-tRNA synthetase (YRS) polypeptides, compositions comprising the same, and methods of using such polypeptides and compositions for treating or diagnosing a variety of conditions.
Description of the Related Art
The term “PEGylation” refers to the modification of biological molecules by covalent conjugation with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer. PEGylation is typically used as a strategy to overcome particular disadvantages associated with some biopharmaceuticals. PEGylation can change the physical and chemical properties of a biological molecule, such as its conformation, electrostatic binding, hydrophobicity, and pharmacokinetic profile. In general, PEGylation improves drug solubility and decreases immunogenicity. PEGylation also increases drug stability and the retention time of the conjugates in blood, and reduces proteolysis and renal excretion, thereby allowing a reduced dosing frequency. In order to benefit from these favorable pharmacokinetic consequences, a variety of therapeutic proteins, peptides, and antibody fragments, as well as small molecule drugs, have been PEGylated.
A number of properties of the PEG polymer—e.g. mass, number of linking chains, the molecular site of PEG attachment—have been shown to affect the biological activity and bioavailability of the PEGylated product. Releasable PEGs have been designed to slowly release the native protein from the conjugates into the blood, aiming at avoiding any loss of efficacy that may occur with stable covalent PEGylation. Since the first PEGylated drug was developed in the 1970s, PEGylation of therapeutic proteins has significantly improved the treatment of several chronic diseases, including hepatitis C, leukemia, severe combined immunodeficiency disease, rheumatoid arthritis, and Crohn's disease.
Tyrosyl-tRNA synthetases (YRS), and fragments and variants thereof, have been shown to possess a variety of non-canonical activities of therapeutic and diagnostic relevance. Examples of such activities include modulation of hematopoietic pathways such as thrombopoiesis, modulation of angiogenesis, and modulation of inflammatory pathways, among others. To best exploit these and other activities in therapeutic or diagnostic settings, there is a need in the art for YRS polypeptides having improved pharmacokinetic properties.
The present invention is focused on the development of PEGylated versions of YRS polypeptides that retain the biological activity of the native YRS polypeptides and exhibit superior pharmacokinetic properties. These improved therapeutic forms of the YRS polypeptides enable the development of more effective therapeutic regimens for the treatment of various diseases and disorders, and require significantly less frequent administration than the unmodified proteins.
These improved methods are based, at least in part, on animal studies and in vitro studies that surprisingly demonstrate that PEGylated versions of the YRS polypeptides actually exhibit enhanced biological activity compared to the native molecules, while also exhibiting vastly superior pharmacokinetic characteristics.